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Generalized binomial -leap method for biochemical kinetics incorporating both delay and intrinsic noise

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10.1063/1.2919124

### Abstract

The delay stochastic simulation algorithm (DSSA) by Barrio *et al.* [Plos Comput. Biol.2, 117–E (2006)] was developed to simulate delayed processes in cell biology in the presence of intrinsic noise, that is, when there are small-to-moderate numbers of certain key molecules present in a chemical reaction system. These delayed processes can faithfully represent complex interactions and mechanisms that imply a number of spatiotemporal processes often not explicitly modeled such as transcription and translation, basic in the modeling of cell signaling pathways. However, for systems with widely varying reaction rate constants or large numbers of molecules, the simulation time steps of both the stochastic simulation algorithm (SSA) and the DSSA can become very small causing considerable computational overheads. In order to overcome the limit of small step sizes, various -leap strategies have been suggested for improving computational performance of the SSA. In this paper, we present a binomial -DSSA method that extends the -leap idea to the delay setting and avoids drawing insufficient numbers of reactions, a common shortcoming of existing binomial -leap methods that becomes evident when dealing with complex chemical interactions. The resulting inaccuracies are most evident in the delayed case, even when considering reaction products as potential reactants within the same time step in which they are produced. Moreover, we extend the framework to account for multicellular systems with different degrees of intercellular communication. We apply these ideas to two important genetic regulatory models, namely, the hes1 gene, implicated as a molecular clock, and a Her1/Her 7 model for coupled oscillating cells.

© 2008 American Institute of Physics

Received 03 August 2007
Accepted 11 April 2008
Published online 30 May 2008

Acknowledgments: K.B. would like to thank the Australian Research Council for funding through the Federation Fellowship program.

Article outline:

I. INTRODUCTION

II. DELAY STOCHASTIC SIMULATION ALGORITHM

III. -LEAP METHODS

A. Method 1 (binomial -leap by Tianhai and Burrage)

B. Method 2 (modified binomial -leaping by Peng *et al.*)

C. Method 3 (generalized binomial -leaping)

D. Notes on methods 1–3

E. -leaps with delayed reactions

IV. NUMERICAL SIMULATIONS

A. Simple four-reaction model without delays

B. The Hes1-dimer model

C. The Her1/Her7 model for five coupled cells

V. DISCUSSIONS AND CONCLUSIONS

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2008-05-30

2014-04-19

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